2-Cyano-3-hydroxy-N-(4'-trifluoromethylphenyl)-crotone amide

Description

Teriflunomide (Aubagio®), also known as A77 1726, is an immunosupressant marketed by Sanofi for the teatment of multiple sclerosis (MS). Teriflunomide is the active metabolite of leflunomide, used for treatment of patients diagnosed with rheumatoid arthritis, and therefore simultaneously can be used as a treatment for rheumatoid arthritis.Teriflunomide acts as an inhibitor of the mitochondrial enzyme dihydrorotate dehydrogenase, inhibiting pyrimidine formation, and resulting in reduced B and T cell proliferation.

Chemical properties

White Solid

The Uses of 2-Cyano-3-hydroxy-N-(4'-trifluoromethylphenyl)-crotone amide

The active metabolite of Leflunomide, 2-Cyano-3-hydroxy-N-(4'-trifluoromethylphenyl)-crotone amide can be used as a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis.

Definition

ChEBI: Teriflunomide is an enamide obtained by formal condensation of the carboxy group of (2Z)-2-cyano-3-hydroxybut-2-enoic acid with the anilino group of 4-(trifluoromethyl)aniline. Used for the treatment of relapsing forms of multiple sclerosis and rheumatoid arthritis. It has a role as an EC 1.3.98.1 [dihydroorotate oxidase (fumarate)] inhibitor, a tyrosine kinase inhibitor, a hepatotoxic agent, a drug metabolite and a non-steroidal anti-inflammatory drug. It is a nitrile, an enol, an aromatic amide, an enamide, a member of (trifluoromethyl)benzenes and a secondary carboxamide.

Clinical Use

Immunomodulating agent:
Treatment of relapsing remitting multiple sclerosis

Synthesis

Numerous syntheses of teriflunomide have been developed to date, most relying on the use of 4- trifluoromethyl aniline (167). The current optimized method for scale-up synthesis of teriflunomide, developed by Keshav and coworkers, begins with reaction of commercial 4-trifluoromethyl aniline 167 and ethylacetoacetate (168) in refluxing xylenes, providing acetoamidate 169 in 51% yield . The resulting acetoamidate 169 was then treated with H2O2, KBr, and concentrated HCl at room temperature, providing bromide 170 in 67% yield. Bromide 170 was reacted with NaCN in DMSO, generating teriflunomide (XXVI) in 85% yield.

Drug interactions

Potentially hazardous interactions with other drugs
Lipid-lowering agents: effect significantly reduced by colestyramine - avoid; concentration of rosuvastatin increased - consider reducing rosuvastatin dose.
Live vaccines: risk of generalised infections - avoid.

Metabolism

Teriflunomide is the active metabolite of leflunomide. It is moderately metabolised and teriflunomide is the only component detected in plasma. The main biotransformation pathway is hydrolysis with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation. Teriflunomide is excreted in the gastrointestinal tract mainly through the bile as unchanged drug and most likely by direct secretion.

storage

Store at +4°C

References

1) Manna et al. (1999), Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression; J. Immunol., 162 2095 2) Davis et al. (1996), immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase; Biochemistry, 35 1270 3) Seah et al. (2008), Oxidative bioactivation and toxicity of leflunomide in immortalized human hepatocytes and kinetics of the non-enzymatic conversion to its major metabolite, A77 1726; Drug Metab. Lett., 2 153